R&D Day July 13, 2016 Ionis: Creating Value Three - - PowerPoint PPT Presentation

July 13, 2016

R&D Day

Ionis: Creating Value

Mid-term Near-term

Three groundbreaking Phase 3 drugs close to commercialization

Long-term

Advanced, diverse pipeline of first-in- class medicines of high value for patients with significant unmet medical need Ionis innovations in technology broaden utility and enhance value of platform

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Three Groundbreaking Medicines Close to Commercialization

IONIS-TTRRx Nusinersen

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Volanesorsen

Volanesorsen

For Familial Chylomicronemia Syndrome (FCS) and Familial Partial Lipodystrophy (FPL)

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Volanesorsen: For Severe, Triglyceride-driven Orphan Diseases with No Treatment Today

Potential to improve the life-altering, and in many cases life- threatening, manifestations of FCS and FPL Significant near-term commercial opportunity First and only drug to specifically and robustly reduce Apolipoprotein C-III (ApoCIII) to dramatically decrease triglycerides

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Two Life-threatening, Genetic, Orphan Diseases Marked by Extreme Triglyceride Levels

No adequate treatments available Risk of potentially fatal pancreatitis FPL

• ~3-5k patients worldwide
• Inability to store fat, resulting in

triglycerides in the 1,000s

• Disturbance of adipose tissue

storage resulting in physical abnormalities

• Extreme insulin resistance, T2DM
• Premature death from

pancreatitis, liver cirrhosis and cardiovascular disease

FCS

• ~3-5k patients worldwide
• LPL deficiency, resulting in

triglycerides in the 1,000s

• Inability to metabolize and clear

triglyceride packets resulting in chronic pancreatitis

• Metabolic abnormalities,

increased risk of diabetes

• Severe lipemia in blood

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Volanesorsen: Ideal Profile as a Potential Treatment for Patients with FCS and FPL

 In FCS patients reduced triglyceride levels up to 86%  Only drug to specifically lower ApoCIII  Improved glucose control, insulin sensitivity  Improved lipid profile including increased HDL-cholesterol

• 71% to -88%
• 64% to -71%
• 11% to -58%

+42% to +78%

Mean Changes ApoCIII

TG

Non- HDL-C

HDL-C

Good Cholesterol

Nusinersen

For Patients with Spinal Muscular Atrophy (SMA)

Nusinersen is Positioned to be the First and Best-in-class Therapy for Infants and Children with SMA

SMA is a rare, severe genetic neuromuscular disease defined by progressive muscle atrophy and loss of motor function Ongoing Phase 2 studies show improvements in survival and continued achievement of motor milestones compared to natural history Phase 3 studies in infants and children with SMA fully enrolled and data expected by H1:17 Ionis and Biogen are committed to bringing nusinersen to the market as quickly as possible

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SMA: Progressive Muscle Atrophy Caused by Genetic Defects in the SMN1 Gene

• Number one genetic cause of

infant death

• Absent of supportive care, most

infants will never see their 2nd birthday

Infantile Onset

• Shortened life expectancy
• Difficulty sitting, raising arms,

lifting, standing and walking

Childhood Onset

No currently approved therapies

– Miller, Survived 87 days – Peter

~30-35k patients worldwide for all forms of SMA

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Robust Development Plan to Support Commercialization of Nusinersen

Infant Onset Pre- symptomatic Newborns Childhood Onset

Biogen Study Phase 3 Biogen Study OLE Study for Phase 3 Studies Phase 3 Phase 2 Open Label

(Infants)

Phase 2 Open Label

(Children)

Global Commercial Opportunity

Infant and Childhood Onset

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IONIS-TTRRx

Toward a Treatment for Patients with Transthyretin (TTR) Amyloidosis

Severe, Progressive and Fatal Disease

TTR Amyloidosis

One Disease Caused by the Formation of TTR Amyloid Deposits Leading to Organ Failure

• ~10k patients worldwide
• Age of onset: 30 – 50
• TTR amyloid primarily

infiltrates peripheral nerves

• Loss of nerve function
• Multi-organ failure
• Fatal in 5 – 15 years

FAC

• ~40k patients worldwide
• Age of onset: 60 – 70 years

Wild-type

• ~200k patients worldwide
• Age of onset: >70 years

– Fabio – Dawn – Eric

FAP TTR Cardiomyopathy

• TTR amyloid primarily

infiltrates the heart

• Congestive heart failure
• Fatal in 3 – 5 years

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IONIS-TTRRx: Potentially First-in-class and Best-in- class Drug to Treat All Forms of TTR Amyloidosis

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TTR amyloidosis is a progressive, debilitating, fatal disease caused by TTR amyloid deposits leading to multi-organ failure IONIS-TTRRx is close to potential filing and launch for patients with familial amyloid polyneuropathy (FAP) Evidence of disease stabilization in patients with TTR cardiomyopathy from an investigator-initiated Phase 2 study GSK is the right development and commercial partner for IONIS-TTRRx

Robust Phase 3 NEURO-TTR study design

• Includes stage 1 and 2 FAP patients with a broad range of genotypes
• Majority of patients have both polyneuropathy and cardiomyopathy
• Cardiomyopathy analyses will provide data on cardiovascular endpoints

Robust and sustained TTR knockdown in patients

• Maximum TTR reductions of up to 95%

NEURO-TTR Study Summary

Safety and tolerability profile supports continued development

• Study on-track to complete in H1:17
• Strong patient retention in NEURO-TTR and robust participation in the OLE
• Injection site reactions occurring in approximately 1% of all injections, which

were predominantly mild

• Very low incidence of serious platelet declines observed in NEURO-TTR
• Patients treated over 3 years (and continuing)

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Ionis Pipeline

Value Beyond the Phase 3 Programs

Richard Geary, Ph.D., Senior Vice President, Development

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Phase 2 Pipeline Poised to Deliver a Broad Range of Transformative Medicines

IONIS-DMPK-2.5Rx Myotonic Dystrophy 1 Biogen IONIS-HTTRx Huntington’s Disease Roche IONIS-SOD1Rx Amyotrophic Lateral Sclerosis Biogen IONIS-APO(a)-LRx Hypolipoproteinemia(a) with Premature CVD with Recurrent MACE Ionis/Akcea IONIS-ANGPTL3-LRx Rare Mixed Dyslipidemias Ionis/Akcea IONIS-FXIRx Clotting Disorders Bayer IONIS-APO(a)-LRx Hypolipoproteinemia(a) with CAVS Ionis/Akcea IONIS-APO(a)-LRx Hypolipoproteinemia(a) with CV Risk Ionis/Akcea IONIS-ANGPTL3-LRx Mixed Dyslipidemias Ionis/Akcea IONIS-AR-2.5Rx Cancer Ionis IONIS-STAT3-2.5Rx Cancer AstraZeneca

CV Severe and Rare

Onco

Drugs Indication Partner Phase I Phase II Phase III

IONIS-GCGRRx Diabetes Ionis IONIS-GCCRRx Diabetes Ionis IONIS-PTP1BRx Diabetes Ionis IONIS-FGFR4Rx Obesity Ionis

Metabolic

All Programs in Position to Advance to Phase 3 within the Next 1-3 Years

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First and only antithrombotic to disassociate prevention of thrombotic events and bleeding risk IONIS-FXIRx demonstrated a 7-fold lower incidence in VTE in patients undergoing total knee replacement* Well tolerated with no flu-like symptoms and infrequent, mild injection site reactions Commercial potential in wide array of therapeutic settings for which other anticoagulants are not currently effective

*Incidence of venous thromboemboli compared to patients treated with enoxaparin undergoing total knee replacement

IONIS-FXIRx: Towards a Safer and More Effective Antithrombotic

Generation 2+ Antisense Drug

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Potential first-in-class and best-in-class glucagon receptor (GCGR) inhibitor for patients with severe diabetes >2% reduction in HbA1c at 75mg dose and >1% at 50mg dose

• bserved in ongoing Phase 2 study

Significant glucose control achieved at lower weekly doses with minimal GCGR-related liver enzyme elevations Well tolerated with no flu-like symptoms and infrequent, mild injection site reactions

IONIS-GCGRRx: A Promising New Therapeutic Approach for Type 2 Diabetes

Generation 2+ Antisense Drug

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First and only program to selectively and robustly reduce Lp(a), a key driver of cardiovascular disease LICA technology in IONIS-APO(a)-LRx increases potency and allows for lower doses and flexibility in dosing frequency Well tolerated with no flu-like symptoms and no injection site reactions observed to date Multi-billion dollar commercial potential targeting both rare and broad patient populations

IONIS-APO(a)-LRx: The Next Frontier in Cardiovascular Disease Management

LICA Drug

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Significant Ongoing Progress in Our Oncology Franchise

IONIS-STAT3-2.5Rx IONIS-AR-2.5Rx

Multiple durable clinical responses in heavily pre-treated patients, including 2 complete responses

MD Anderson Cancer Center

Multiple durable PSA responses with prolonged stable disease in heavily pre- treated patients with metastatic castration resistant prostate cancer (CRPC) Strategic partnership provides access to MDACC’s novel, traditionally undruggable cancer targets

Key Clinical Data Planned in 2016 and Early 2017

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Q3:16 Q4:16

• Ph. 3 Events H1:17

IONIS-TTRRx: Ph. 2 Data in ATTR-CM (Benson) IONIS-TTRRx: Ph. 3 Data Update in FAP OLE IONIS-DMPK-2.5Rx:

• Ph. 1/2 (MAD) Data

IONIS-DGAT2Rx:

• Ph. 1 Data

IONIS-ANGPTL3-LRx:

• Ph. 2 Data

Nusinersen: Ph. 3 Data for CHERISH Volanesorsen: Ph. 3 Data for FCS Nusinersen: Ph. 3 Data for ENDEAR IONIS-TTRRx: Ph. 3 Data for NEURO-TTR IONIS-FXIRx:

• Ph. 2 Data

IONIS-STAT3-2.5Rx:

• Ph. 2 Data

IONIS-AR-2.5Rx

• Ph. 2 Data

IONIS-GSK4-LRx

• Ph. 1 (SAD) Data

IONIS-GCGRRx

• Ph. 2 Data (Interim)

IONIS-APO(a)-LRx

• Ph. 2 Data

      

IONIS-FGFR4Rx:

• Ph. 2 Data

Ionis Technology: Creating Better Medicines and Expanding Opportunities

Stanley Crooke, M.D., Ph.D., CEO and Chairman

Advances in our Technology in the Pipeline Today

Gen 2+ Gen 2.5 LICA LICA

Continued Investment in Core Antisense Research

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Large Safety Database Provides Evidence of Good Safety Profile of 2nd Generation Antisense Drugs

• Large clinical safety database (Ionis safety experience)
• >6,000 patients treated with Ionis 2nd Generation antisense drugs (iv/sc)
• Doses: 0.6-15 mg/kg
• >3,000 patients in the integrated safety database
• Integrated safety database:
• No platform generic liver or renal toxicities identified
• No platform generic platelet toxicities identified
• No platform safety issues identified in clinical studies for the following

systems:

• Cardiac, CNS, muscle, hematology, liver, kidney
• No clinically significant drug-drug interactions observed
• Lack of P450 metabolism interactions
• Lack of major transporter interactions

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Generation 2.5 Broadens Utility and Value of Antisense Technology

1 2 3 4 3 4

Enhanced affinity for target sequence Up to 10-fold increase in potency Enhanced target engagement in new tissues, i.e. stromal cells, muscle cells Good tolerability observed in clinical studies

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Advances in Ionis Technology are Translating into Real Value in the Pipeline Today

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Drugs Indication Phase

IONIS-DMPK-2.5Rx Myotonic Dystrophy 1

• Ph. 2

IONIS-STAT3-2.5Rx Cancer

• Ph. 2

IONIS-AR-2.5Rx Cancer

• Ph. 2

IONIS-RHO-2.5Rx Autosomal Dominant Retinitis Pigmentosa PC

Oncology

4 Generation 2.5 Drugs in Clinical Development

Severe & Rare

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LICA is a Game Changing Advance in the Potency of Ionis’ Antisense Drugs

1 2 3 4 3 4

Ultra-low dose Easy to administer, flexible dosing: weekly, monthly, quarterly or less frequently Good tolerability observed in clinical studies

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>30-fold more potent in humans as demonstrated by Ionis’ first LICA drug

Advances in Ionis’ Technology are Translating into Real Value in the Pipeline Today

Drugs Indication Phase

IONIS-APO(a)-LRx Hyperlipoproteinemia(a) with premature CVD with recurrent MACE

• Ph. 2

IONIS-ANGPTL3-LRx Rare Mixed Dyslipidemias Mixed Dyslipidemias

• Ph. 2

IONIS-GSK4-LRx Ocular Disease

• Ph. 1

IONIS-HBV-LRx HBV

• Ph. 1

IONIS-GHR-LRx Acromegaly PC IONIS-TMPRSS6-LRx β-Thalassemia PC IONIS-AGT-LRx Treatment-Resistant Hypertension PC IONIS-APOCIII-LRx Severely High TGs PC

Cardiovascular

8 LICA Drugs in Clinical Development

Other Severe & Rare

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Continued Investment in Core Antisense Research Broadens the Utility of Ionis Medicines

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Potential for 1-5 mg dose per week Ultra-low doses for patients has potential to broaden addressable patient populations 1st development candidate planned for late 2016/ early 2017

Generation 2.5 + LICA Broadens Utility and Value of Antisense Technology

1 2 3 3

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Advances in Ionis’ Technology Greatly Expand

• ur Ability to Treat Disease

Generation 2+ Generation 2.5 Enhances potency and tolerability LICA Enhances target engagement in new tissues Dramatically and additively improves potency in liver and now other tissues Generation 2.5 + LICA Enables very low dose volumes

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New Antisense Mechanisms Broadens applicability and enhances value of platform

Partners' Extensive R&D Activities Support Robust Pipeline

• Researching novel

delivery methods

• Researching

antisense medicines to treat metabolic cardiovascular and renal diseases

• Performing clinical

and pre-clinical studies

• Initiated 2 Phase 2

studies for nusinersen

• Contributing

significantly to core antisense research

• Researching and

developing antisense medicines to treat neuro diseases

• Initiating Phase 2 for

IONIS-HBV-LRx and Phase 2 for IONIS- HBVRx

• Researching oral

formulation of antisense medicines to treat autoimmune disorders of the GI tract

• PoC work in animal

models

• Conducting

biomarker work to support IONIS- HTTRx development plan

• Developing

IONIS-FXIRx broadly for the prevention of thrombosis

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Revenue 2012 – 2015

Ionis Has Built a Strong Financial Foundation

Pro Forma Operating Loss 2012 – 2015 Profitable in 6 Quarters Since the Beginning of 2012

($100) ($80) ($60) ($40) ($20) $0

2012 2013 2014 2015

2015

Sustainable Revenue and Cash Base from Partnerships

Cash 2012 – 2015

$374M $657M $729M $779M

$0 $100 $200 $300 $400 $500 $600 $700 $800 $900

2012 2013 2014 2015 2015 233 $102M $147M $214M $284M

$0 $50 $100 $150 $200 $250 $300 2012 2013 2014 2015E

2015

Ionis’ Future Focused on Value

2017 / 2018 Launch Potential

Nusinersen IONIS-TTRRx Volanesorsen

~30,000 – 35,000 Patients Worldwide

(Initial indication is subset of total patients worldwide)

~10,000 Patients for Initial Indication ~250,000 Patients Worldwide ~3,000 – 5,000 Patients for Initial Indication ~6,000 – 10,000 Patients Worldwide Responsible for 100% of Launch Cost* Responsible for 100% of Launch Cost* Ionis & Akcea Responsible for 100% of Launch Cost Pre-launch Milestones & Licensing Revenue Tiered Royalty Rate Up to the Mid-teens Pre-launch Milestones & Licensing Revenue Tiered Royalty Rate Up to the Mid-teens Retain 100% of Revenue

*If option to license is exercised

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